Abstract Down syndrome (DS), known as trisomy 21, is the most common chromosomal disorder in newborns. The number of babies born with DS is increasing, with about 1 in every 700 babies being born with DS in the United States (US). Patients with DS carry an extra complete or partial chromosome 21, disrupting numerous processes, including cardiac, digestive, and neural systems, with cognitive impairment being one of the most notable features. Patients with DS have problems with learning, memory, and speech/language throughout life, as well as an early onset of Alzheimer's disease. Given that DS patients live longer than before as a result of improved medical care, and in view of the fact that the concept of locus minoris resistentiae is still valid, it is critical to study the altered initial states of brain development in DS for the purpose of better predicting what aspects of brain function will preferentially and precociously deteriorate; this would allow for earlier and better prevention and treatment. However, detailed, comprehensive knowledge of early development of cortical anatomy and fiber pathways in DS patients is still lacking. The brain abnormalities in DS begin in utero; fewer neurons are generated and migrate to wrong destinations. By 15 gestational weeks (GW), brains with DS have abnormal cortical thickness, with volumes that are 80% of those of typically developing brains. However, much more detailed information is needed, and we now have the tools to make direct anatomical observation on fetal and early postnatal DS brains. We have extensive experience, both in ex vivo and in vivo, magnetic resonance imaging (MRI) of human brains. We have established that high-angular resolution diffusion MRI (HARDI) with optimal parameters has the potential to define the connectional anatomy of developing human fetal, newborn, and infant brains. We have reported, with unprecedented details, spatiotemporal developmental patterns of the majority of axonal tracts, as well as regional regression patterns of neuronal migration pathways using diffusion MRI tractography. In fetal ages, transient zones (e.g., future cortical gray matter, cortical plate [CP]; future white matter, intermediate zone [IZ]) continuously change their morphology, reflecting neuronal proliferation/migration, and axonal elongation, maturation, and pruning, and could provide critical biomarkers for normal/abnormal brain development. Through recent preliminary MRI investigations in typically developing brains, we have observed migration and axonal pathways terminating in different transient zones, not randomly but with unique spatiotemporal patterns. Based on the demonstrated anomalies in the gross morphology of the DS brain, together with what is already known about metric changes in the cortex and white matter, we hypothesize that early brain development in DS will show regionally differential spatiotemporal patterns as compared to that in controls.